The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. ...While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.
► Muscleblind-like 2 regulates alternative splicing in the brain ► Developmental regulation of splicing is disrupted in Mbnl2 knockout mice ► RNAs targeted by MBNL2 are misspliced in the myotonic dystrophy brain
Myotonic dystrophy, a disease caused by toxic RNAs, profoundly affects brain function. In this Article, Charizanis et al. demonstrate that the effect on brain function results from loss of muscleblind-like 2 RNA splicing regulation during brain development.
Recurrent attacks of optic neuritis and myelitis are the hallmarks of both neuromyelitis optica (NMO) and multiple sclerosis (MS). NMO immunoglobulin G (NMO-IgG), which recognizes astrocytic ...aquaporin-4 (AQP4) water channels, is a specific serum autoantibody that distinguishes NMO from MS. The pathogenic role of the anti-AQP4 antibody (AQP4-Ab, NMO-IgG) in NMO has been speculated based on several studies in vitro. The aim of this study was to demonstrate the pathogenicity of AQP4-Ab in vivo. We obtained IgG from patients who underwent therapeutic plasmapheresis, and developed an animal model by passive transfer of IgG to rats. The active lesions of the rats exhibited pathological characteristics strikingly similar to those of NMO, marked by astrocytic loss and perivascular deposition of immunoglobulin and complements. These findings provide the first evidence of the pathogenicity of AQP4-Ab in vivo and support the therapeutic efficacy of eliminating the antibodies by plasmapheresis.
Aim
The relationship of Helicobacter pylori infection with periodontitis was examined.
Methods
The study subjects were 686 individuals (males 504, females 182; mean age 53.8 years) who underwent a ...screening test for periodontitis between April 2015 and March 2018 and whose H. pylori infection status could be determined. The periodontitis test was performed by examining saliva concentrations of lactate dehydrogenase and hemoglobin (Hb), with a lactate dehydrogenase level ≥ 350 U/L and/or hemoglobin level ≥ 2 μg/mL defined as positive for periodontitis.
Results
Among subjects found positive in screening for periodontitis, those classified as negative and positive for H. pylori infection, as well as post‐eradicated were 81 (39.7%), 30 (14.7%), and 93 (45.6%), respectively, while those among subjects shown negative for periodontitis numbered 241 (50.0%), 52 (10.8%), and 189 (39.2%), respectively. Subjects noted as negative, positive, and post‐eradicated for H. pylori infection comprised 25.2%, 36.6%, and 32.9%, respectively, of all shown positive for periodontitis. Multiple logistic regression analysis indicated that the risk for positive in the periodontitis test was higher among subjects with H. pylori infection as compared with those without, while post‐eradicated status tended to reduce that risk. Repeated examinations performed following H. pylori eradication showed that the number of subjects positive for periodontitis was decreased among those who underwent successful eradication.
Conclusion
Helicobacter pylori infection increases the risk for occurrence of periodontitis, which can be reduced by successful eradication.
Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as ...muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain.
Purpose
The word “fixel” refers to the specific fiber population within each voxel, and fixel-based analysis (FBA) is a recently developed technique that facilitates fiber tract-specific statistical ...analysis. The aim of the paper is to apply FBA to detect impaired fibers for corticobasal syndrome (CBS) especially in regions that contain multiple crossed fibers.
Methods
FBA was performed in cohorts of participants clinically diagnosed with CBS (
n
= 10) and Parkinson’s disease (
n
= 15) or in healthy controls (
n
= 9). The parameters of the diffusion weighted image were echo time, 83 ms; time, 8123.6 ms; flip angle, 90°; section thickness, 2 mm;
b
= 1000 s/mm
2
; and 32 axes. Diffusion tensor analysis was conducted using tract-based spatial statistics (TBSS), and white matter volume was estimated via voxel-based morphometry.
Results
A comparison of PD or HC to CBS revealed a significant difference in the dentatorubrothalamic tract of the brainstem in FBA in addition to the affected regions in voxel-based morphometry and TBSS (family-wise error-corrected
p
< 0.05). Reduction of the white matter fibers crossing the brainstem could not be detected via microstructural changes identified using TBSS, but it was detected using FBA.
Conclusion
FBA has some advantages in determining the distribution of corticobasal syndrome lesions.
This study aimed to evaluated the clinical impact of adding 11C Pittsburgh compound-B (11C-PiB) PET for clinical diagnosis of mild cognitive impairment (MCI) to Alzheimer's disease (AD) ...dementia.Twenty six (mean age 78.5 ± 5.18 years, 21 females) AD (n = 7), amnestic MCI (n = 12), non-amnestic MCI (n = 3), vascular dementia, progressive supranuclear palsy (PSP) with frontotemporal dementia (FTD), FTD (n = 1 each), and normal (n = 1) patients underwent 11C-PiB-PET, MRI, and SPECT scanning. 11C-PiB-PET was compared with MRI and SPECT for clinical impact.11C-PiB-PET showed positivity in 6, 9, and 0 of the AD, amnestic MCI, and non-amnestic MCI patients, respectively, and 0 of those with another disease. Parahippocampal atrophy at VSASD was observed in 5 AD patients, 6 amnestic and PiB-positive MCI patients, 1 amnestic and PiB-negative MCI patient, and 1 vascular dementia patient. Parietal lobe hypoperfusion in SPECT findings was observed in 6, 4, and 2 of those, respectively, as well as 1 each of non-amnestic MCI, vascular dementia, and normal cases. Sensitivity/specificity/accuracy for selecting PiB-positive patients among the 15 MCI patients for 11C-PiB-PET were 100% (9/9)/100% (6/6)/100% (15/15), for VSRAD were 66.7% (6/9)/83.3% (5/6)/73.3% (11/15), and for SPECT were 44.4% (4/9)/50.0% (3/6)/46.7% (7/15), while those were 88.9% (8/9)/33.3% (2/6)/66.7% (10/15)/for combined VSRAD and SPECT. 11C-PiB-PET accuracy was significantly higher than that of SPECT.11PiB-PET alone may be useful for selecting patients who will progress from MCI to AD in the future, although follow-up study is necessary to clarify the outcome of MCI patients.
Increasing evidence shows that administration of bone marrow mononuclear cells (BMMCs) is a potential treatment for various ischemic diseases, such as ischemic stroke. Although angiogenesis has been ...considered primarily responsible for the effect of BMMCs, their direct contribution to endothelial cells (ECs) by being a functional elements of vascular niches for neural stem/progenitor cells (NSPCs) has not been considered. Herein, we examine whether BMMCs affected the properties of ECs and NSPCs, and whether they promoted neurogenesis and functional recovery after stroke. We compared i.v. transplantations 1 x 10(6) BMMCs and phosphate-buffered saline in mice 2 days after cortical infarction. Systemically administered BMMCs preferentially accumulated at the postischemic cortex and peri-infarct area in brains; cell proliferation of ECs (angiogenesis) at these regions was significantly increased in BMMCs-treated mice compared with controls. We also found that endogenous NSPCs developed in close proximity to ECs in and around the poststroke cortex and that ECs were essential for proliferation of these ischemia-induced NSPCs. Furthermore, BMMCs enhanced proliferation of NSPCs as well as ECs. Proliferation of NSPCs was suppressed by additional treatment with endostatin (known to inhibit proliferation of ECs) following BMMCs transplantation. Subsequently, neurogenesis and functional recovery were also promoted in BMMCs-treated mice compared with controls. These results suggest that BMMCs can contribute to the proliferation of endogenous ischemia-induced NSPCs through vascular niche regulation, which includes regulation of endothelial proliferation. In addition, these results suggest that BMMCs transplantation has potential as a novel therapeutic option in stroke treatment.
Dental erosion (DE), one of oral hard tissue diseases, is one of the extraoesophageal symptoms defined as the Montreal Definition and Classification of gastroesophageal reflux disease (GERD). ...However, no study evaluated the relationship between GERD and oral soft tissues. We hypothesized that oral soft tissue disorders (OSTDs) would be related to GERD. The study aimed to investigate the association OSTDs and GERD.
GERD patients (105 cases), older and younger controls (25 cases each) were retrospectively examined for oral symptoms, salivary flow volume (Saxon test), swallowing function (repetitive saliva swallowing test RSST), teeth (decayed, missing, and filled DMF indices), and soft tissues (as evaluation of OSTDs, gingivitis; papillary, marginal, and attached PMA gingival indexes, simplified oral hygiene indices OHI-S, and inflammatory oral mucosal regions). Clinical histories, which included body mass index BMI, the existence of alcohol and tobacco use, and bruxism, were also investigated. A P value of <0.05 was defined as statistically significant.
GERD patients, older and younger controls participated and aged 66.4 ± 13.0, 68.3 ± 8.2 and 28.7 ± 2.6 years old, respectively. The most common oral symptom in the GERD patients was oral dryness. Salivary flow volume and swallowing function in the GERD patients were significantly lower than in either of the controls (all P < 0.05). Inflammatory oral mucosal regions were found only in the GERD patients. The DMF indices, as a measure of dental caries, in the GERD patients were higher than in the younger controls (P < 0.001), but lower than in the older controls (P = 0.033). The PMA gingival indexes, as a measurement for gingival inflammation, and OHI-S, as a measure for oral hygiene, in the GERD patients were significantly higher than in either of the controls (all P < 0.05). Though no significant differences in BMI, the existence of alcohol and tobacco use were found, bruxism, as an exacerbation factor of periodontal disease, in the GERD patients was significantly more frequent than in either control group (P = 0.041).
OSTDs were associated with GERD, which was similar to the association between DE and GERD.
Transplantation of neural stem cells (NSCs) has been proposed as a therapy for a range of neurological disorders. To realize the potential of this approach, it is essential to control survival, ...proliferation, migration, and differentiation of NSCs after transplantation. NSCs are regulated in vivo, at least in part, by their specialized microenvironment or "niche." In the adult central nervous system, neurogenic regions, such as the subventricular and subgranular zones, include NSCs residing in a vascular niche with endothelial cells. Although there is accumulating evidence that endothelial cells promote proliferation of NSCs in vitro, there is no description of their impact on transplanted NSCs. In this study, we grafted cortex-derived stroke-induced neural stem/progenitor cells, obtained from adult mice, onto poststroke cortex in the presence or absence of endothelial cells, and compared survival, proliferation, and neuronal differentiation of the neural precursors in vivo. Cotransplantation of endothelial cells and neural stem/progenitor cells increased survival and proliferation of ischemia-induced neural stem/progenitor cells and also accelerated neuronal differentiation compared with transplantation of neural precursors alone. These data indicate that reconstitution of elements in the vascular niche enhances transplantation of adult neural progenitor cells.
Background
This preliminary clinical study aimed to evaluate the effects of salivary flow volume and swallowing function on oral symptoms including dental erosion in gastroesophageal reflux disease ...(GERD).
Methods
The subjects were 40 GERD patients and 30 (15 younger, 15 older) healthy controls. Detailed medical, dietary, and dental histories were obtained to identify individual behavioral habits potentially associated with dental erosion. Oral examination evaluated dental erosion and determined scores for the decayed, missing, filled (DMF) index, the papillary, marginal, attached (PMA) index for gingivitis, and the Simplified Oral Hygiene Index (OHI-S). Salivary flow volume and swallowing function were evaluated by the Saxon test and repetitive saliva swallowing test, respectively.
Results
The DMF index and OHI-S scores differed significantly between all 3 groups. The PMA index was significantly different between the GERD group and the two control groups. The prevalence of dental erosion was 24.3% in the GERD group (0% in the control groups). No specific relationship was found between the incidence of dental erosion and dietary history or behavioral habits. The Saxon test results were significantly lower in the GERD group than in both the control groups. Frequency of swallowing was significantly lower and time to first swallow was significantly longer in the GERD group than in the two control groups.
Conclusions
Oral symptoms in GERD are likely to be associated with impaired salivary flow volume or swallowing function. Treatment for the oral dryness induced by reduced salivary flow volume and rehabilitation for swallowing function could be indicated in patients with GERD.
PDF
